rs267608188

Variant names:

• chr8-76983340-CAAGTA-C
• rs267608188
• NM_000318.3:c.834_838delTACTT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000318.3(PEX2):​c.834_838delTACTT​(p.Phe278LeufsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. F278F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX2 NM_000318.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 8.73
• Publications: 1 publications found

Genes affected

PEX2 (HGNC:9717): (peroxisomal biogenesis factor 2) This gene encodes an integral peroxisomal membrane protein required for peroxisome biogenesis. The protein is thought to be involved in peroxisomal matrix protein import. Mutations in this gene result in one form of Zellweger syndrome and infantile Refsum disease. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

PEX2 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 5A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• peroxisome biogenesis disorder 5B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0915 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-76983340-CAAGTA-C is Pathogenic according to our data. Variant chr8-76983340-CAAGTA-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 371741.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000318.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX2	NM_000318.3	MANE Select	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift	Exon 4 of 4	NP_000309.2
	PEX2	NM_001079867.2		c.834_838delTACTT	p.Phe278LeufsTer3	frameshift	Exon 3 of 3	NP_001073336.2
	PEX2	NM_001172086.2		c.834_838delTACTT	p.Phe278LeufsTer3	frameshift	Exon 5 of 5	NP_001165557.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX2	ENST00000357039.9	TSL:1 MANE Select	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift	Exon 4 of 4	ENSP00000349543.4
	PEX2	ENST00000522527.5	TSL:1	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift	Exon 3 of 3	ENSP00000428638.1
	PEX2	ENST00000520103.5	TSL:2	c.834_838delTACTT	p.Phe278LeufsTer3	frameshift	Exon 3 of 3	ENSP00000428590.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Peroxisome biogenesis disorder 5A (Zellweger) (2)
1	-	-	Peroxisome biogenesis disorder 5B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267608188; hg19: chr8-77895576;